Migraine is a common, underdiagnosed, and undertreated neurological disorder. Although migraine is the most common cause of severe, recurring headache, headache is only one of them any ways the disease manifests itself. Migraine may also include visual disturbances, alterations in consciousness, photophobia, or phonophobia. The condition can be truly debilitating and the pain can interfere with a person's ability to live a normal productive life. Indeed, attacks can force the sufferer to abandon everyday activities for up to 3 day. Even in symptom-free period, sufferers may live in fear of the next attack.
More than 23 million Americans older than 12 years of age experience migraine, with a 17.6% prevalence in females and 5.7% in males. Given the high prevalence of sufferers, it is not surprising that American businesses lose upwards of 50 billion dollars annually because of absenteeism, reduced worker productivity, and medical expenses secondary to migraine. Thus, the economic and social consequences of migraine are enormous.
Of the different types of migraines, classical migraine (migraine with aura) and common migraine (migraine without aura) are the two most prevalent. Although migraine is caused by intermittent brain dysfunction, the precise pathophysiological mechanisms involved are not understood.
Drugs that have been used in an attempt to treat migraine include: ergotamine and ergotamine-like agents; serotonin agonists; and caffeine with ergots or other pharmacologic agents (see e.g., Silberstein, S. D., Curr. Opinion Neurology 7:258-263 (1994); Welch, K. M. A., New Engl J. Med. 329:1476-1483 (1993); Dumar, K. L., J. Gen. Int. Med. 9:339-348 (1994); Saadah, H., Headache 32:95-97 (1992); and Becker, Arzneimittelforshung (42(4):552-555 (1992)). All of these drugs are thought to initially relieve migraine-associated pain by causing vasoconstriction. Unfortunately, this leads to numerous side effects such as chest pain or pressure, flushing, generalized tingling sensations, nausea, vomiting, pain in the legs and arms, asthenia, drowsiness, and dizziness. Acute ergotism is a particularly pernicious side effect of ergot drugs and is characterized by severe central and peripheral vasoconstriction, nausea, vomiting, diarrhea, colic, headache, vertigo, paresthesia, and possibly convulsive seizures.
Patients have, on occasion, found total or partial relief for some forms of migraine through the use of non-prescription analgesics. As outlined by Welch (New Engl J. Med. 329: 1476-1483 (1993)), the initial dosages of such analgesics are typically: aspirin, 500-650 mg; acetaminophen, 500 mg; naproxen sodium, 750-825 mg; tolfenamic acid, 200-400 mg; and, ibuprofen 200 mg. However, the absorption of these and other agents during a migraine attack has been shown to be impaired, apparently due to gastric stasis.
While significant advances have been made in dealing with migraine, none has proven to be broadly effective for an extended time frame, since the side effects associated with the various options limits their value.
Clearly, there is a need in the art for an effective migraine treatment. Ideally a migraine drug formulation should be nonaddictive and free of vasoactive agents. This requires the exclusion of ergots, serotonin agonists such as sumatriptan, and caffeine. The formulation should relieve or eliminate migraine symptoms, and should be effective when used for acute treatment or when used prophylactically. The invention disclosed herein meets these and other needs. The current invention is based, at least in part, on the surprising discovery that glucocorticoid receptor antagonists are effective agents for the treatment of migraine.
Corticosteroids are steroid hormones released by the adrenal glands. The most significant human adrenal corticosteroids are cortisol, corticosterone and aldosterone. Corticosteroids produce cellular effects following binding to receptors located in the cytoplasm of the cell. Two general classes of corticosteroid receptors are now recognized, the mineralocorticoid receptors (also termed type I, or MR) and the glucocorticoid receptors (also termed type II, or GR).
Mineralocorticoid receptors (MRs) bind cortisol with ten-fold higher affinity than glucocorticoid receptors (GRs) bind glucocorticoids. Thus, the activation of the two classes of receptors may differ depending on the corticosteroid (cortisol) concentration. Blood levels of the glucocorticoid cortisol vary over a wide range during the day. In general, normal cortisol concentrations in the blood range from about 0.5 nM to about 50 nM; however, in response to stress, cortisol concentration may exceed 100 nM.
Glucocorticoid blockers are agents that block or reduce the effects of glucocorticoids. Such interference with glucocorticoid action may, for example, be due to interference with binding of glucocorticoid agonists to glucocorticoid receptors (GR), or to interference with the action of agonist-bound GR at the cell nucleus, or to interference with expression or processing of gene products induced by the action of agonist-bound GR at the nucleus. Glucocorticoid receptor antagonists (GR antagonists) are compounds which inhibit the effect of the native ligand or of glucocorticoid agonists on GR. One mode of action of GR antagonists is to inhibit the binding of GR ligands to GR. A discussion of glucocorticoid antagonists may be found in Agarwal et al. “Glucocorticoid antagonists”, FEBS Lett., 217:221-226 (1987). An example of a GR antagonist is mifepristone, (11β,17β) 11[4 (dimethylamino) phenyl]-17 hydroxy-17 (1 propynyl)estra-4,9 dien-3 one, also known as RU-486 or RU-38486. See U.S. Pat. No. 4,368,085. Mifepristone binds specifically to GR with an affinity about 18 times that of the affinity of cortisol for GR. GR antagonists may be steroids, such as mifepristone, or non-steroids.
The present inventors have determined for the first time that glucocorticoid receptor antagonists are effective agents for the treatment of migraine. Thus, the present invention fulfills the need for an effective method for the treatment of migraine by providing methods of administering glucocorticoid receptor antagonists to a subject.